NM_001291694.2:c.56C>T

Variant names:

• chr3-15003970-C-T
• NM_001291694.2:c.56C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001291694.2(NR2C2):​c.56C>T​(p.Ser19Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR2C2 NM_001291694.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

Genes affected

NR2C2 (HGNC:7972): (nuclear receptor subfamily 2 group C member 2) This gene encodes a protein that belongs to the nuclear hormone receptor family. Members of this family act as ligand-activated transcription factors and function in many biological processes such as development, cellular differentiation and homeostasis. The activated receptor/ligand complex is translocated to the nucleus where it binds to hormone response elements of target genes. The protein encoded by this gene plays a role in protecting cells from oxidative stress and damage induced by ionizing radiation. The lack of a similar gene in mouse results in growth retardation, severe spinal curvature, subfertility, premature aging, and prostatic intraepithelial neoplasia (PIN) development. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine; by MAPK (size 0) in uniprot entity NR2C2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15143955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2C2	NM_001291694.2	c.56C>T	p.Ser19Leu	missense_variant	Exon 2 of 14	ENST00000425241.6	NP_001278623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2C2	ENST00000425241.6	c.56C>T	p.Ser19Leu	missense_variant	Exon 2 of 14	2	NM_001291694.2	ENSP00000388387.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>T (p.S19L) alteration is located in exon 2 (coding exon 1) of the NR2C2 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the serine (S) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;.;.;T;.;T;.
Eigen	Benign	-0.098
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.0034	D
MutationAssessor	Benign	0.81	.;L;.;L;L;.;L;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.58	N;N;D;N;N;N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.29	T;T;.;T;T;T;T;.
Sift4G	Benign	0.29	T;T;.;T;T;T;T;T
Polyphen		0.0010	.;B;.;.;B;.;B;.
Vest4		0.64, 0.67, 0.65, 0.56, 0.59
MutPred		0.30		Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);Gain of catalytic residue at S19 (P = 0.017);
MVP		0.32
MPC		0.32
ClinPred		0.45	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.19
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-15045477;